title: The RAG2 C terminus suppresses genomic instability and lymphomagenesis.
abstract: Misrepair of DNA double-strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin (Ig) and T cell receptor (Tcr) loci has been implicated in pathogenesis of lymphoid malignancies in humans and in mice. Defects in DNA damage response factors such as ataxia telangiectasia mutated (ATM) protein and combined deficiencies in classical non-homologous end joining and p53 predispose to RAG-initiated genomic rearrangements and lymphomagenesis. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical non-homologous end joining for proper repair, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 carboxy (C) terminus, although dispensable for recombination, is critical for maintaining genomic stability. Thymocytes from 'core' Rag2 homozygotes (Rag2(c/c) mice) show dramatic disruption of Tcrα/δ locus integrity. Furthermore, all Rag2(c/c) p53(-/-) mice, unlike Rag1(c/c) p53(-/-) and p53(-/-) animals, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. We also find these features in lymphomas from Atm(-/-) mice. We show that, like ATM-deficiency, core RAG2 severely destabilizes the RAG post-cleavage complex. These results reveal a novel genome guardian role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2(c/c) p53(-/-) and Atm(-/-) mice.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Deriano
authors.forename: Julie
authors.initials: J
authors.lastname: Chaumeil
authors.forename: Marc
authors.initials: M
authors.lastname: Coussens
authors.forename: Asha
authors.initials: A
authors.lastname: Multani
authors.forename: YiFan
authors.initials: Y
authors.lastname: Chou
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Alekseyenko
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
authors.forename: David B
authors.initials: DB
authors.lastname: Roth
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002872:Chromosome Deletion; D033481:Chromosomes, Mammalian / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D042822:Genomic Instability; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D013950:Thymus Gland / Q000166:cytology; D014178:Translocation, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases